Pumping apparatus with outlet coupled to different spatial positions within the pumping chamber

ABSTRACT

Disclosed is a pumping apparatus ( 200 ) configured for delivering a fluid. The pumping apparatus ( 200 ) comprises a pumping chamber ( 220 ) configured for receiving one or more fluids ( 310, 320 ) in defined proportions and for further delivering the received fluids, an outlet ( 240 ), fluidically coupling to a first position ( 350 ) in the pumping chamber ( 220 ), for outleting the fluid to be delivered, and a channel ( 410 ). The channel ( 410 ) fluidically couples on one side to a second position ( 340 ) in the pumping chamber ( 220 ) and on the other side to the outlet ( 240 ), so that—in operation—a first portion of the delivered fluid as outlet at the outlet ( 240 ) is received from the first position ( 350 ) in the pumping chamber ( 220 ), and a second portion of the delivered fluid as outlet at the outlet ( 240 ) is received from the second position ( 340 ) in the pumping chamber ( 220 ). One of the first ( 350 ) and second ( 340 ) positions is a spatial position within the pumping chamber ( 220 ) where fluid components having a first property would tend to accumulate during operation of the pumping apparatus ( 200 ) if such position were not coupled to the outlet ( 240 ), with such accumulation resulting from variations in the first property.

BACKGROUND ART

The present invention relates to a pumping apparatus configured for delivering a fluid, in particular in a high performance liquid chromatography application.

In high performance liquid chromatography (HPLC), a liquid has to be provided usually at a very controlled flow rate (e.g. in the range of microliters to milliliters per minute) and at high pressure (typically 20-100 MPa, 200-1000 bar, and beyond up to currently 200 MPa, 2000 bar) at which compressibility of the liquid becomes noticeable. For liquid separation in an HPLC system, a mobile phase comprising a sample fluid with compounds to be separated is driven through a stationary phase (such as a chromatographic column), thus separating different compounds of the sample fluid which may then be identified.

The mobile phase, for example a solvent, is pumped under high pressure typically through a column of packing medium (also referred to as packing material), and the sample (e.g. a chemical or biological mixture) to be analyzed is injected into the column. As the sample passes through the column with the liquid, the different compounds, each one having a different affinity for the packing medium, move through the column at different speeds. Those compounds having greater affinity for the packing medium move more slowly through the column than those having less affinity, and this speed differential results in the compounds being separated from one another as they pass through the column.

The mobile phase with the separated compounds exits the column and passes through a detector, which identifies the molecules, for example by spectrophotometric absorbance measurements. A two-dimensional plot of the detector measurements against elution time or volume, known as a chromatogram, may be made, and from the chromatogram the compounds may be identified. For each compound, the chromatogram displays a separate curve or “peak”. Effective separation of the compounds by the column is advantageous because it provides for measurements yielding well defined peaks having sharp maxima inflection points and narrow base widths, allowing excellent resolution and reliable identification of the mixture constituents. Broad peaks, caused by poor column performance, so called “Internal Band Broadening” or poor system performance, so called “External Band Broadening” are undesirable as they may allow minor components of the mixture to be masked by major components and go unidentified.

In chromatography systems configured for combining multiple fluids to form a solvent composition, artifacts in the solvent composition may occur which can have a negative impact on the chromatographic performance. Modern HPLC systems are optimized for fast and efficient operation under ultra-high pressure conditions. This, in turn, calls for reduction in volumes, while at the same time requirements regarding compositional precision increase, so that simple passive solutions adding mixing volumes are not feasible in many applications. However, compositional disturbances in particular on shorter separation length may lead to retention time jitter, but also sometimes the mobile phase composition disturbances can cause artifacts or noise the detector's baseline.

U.S. Pat. No. 4,595,495A discloses a programmable solvent delivery system and process. A rapid motion of the piston injects solvent components to a cylinder and produces turbulent flow of the solvent components into the cylinder, thus assuring thorough mixing of the solvent components without the provision of a separate mixing chamber.

U.S. Pat. No. 6,997,683B2 discloses a high pressure reciprocating pump. The pump cylinder head is machined to enhance the mixing of the solvents and solutes. Mixing is enhanced within a space between the cylinder wall and the piston.

In US2012291531A1, the cylinder of a liquid chromatograph has an inner wall provided with a recess to generate a whirl in the plurality of solvents.

WO2013013717A2, by the same applicant and inventors, discloses an HPLC system with packet-wise proportioning followed by immediate longitudinal mixing.

JPS61258975A discloses a liquid chromatograph with multiple outlet ports exiting from the pumping chamber for releasing air from the pumping chamber. US2013/0091935A1 also discloses a liquid chromatograph with multiple outlet ports exiting from the pumping chamber for accelerating mixing of solvents. Both documents disclose the features of the preamble to claim 1.

DISCLOSURE

It is an object of the invention to provide an improved combining of multiple fluids to form a solvent composition in HPLC applications. The object is solved by the independent claim(s). Further embodiments are shown by the dependent claim(s).

According to the present invention, a pumping apparatus is provided, which is configured for delivering a fluid, preferably a pressurized fluid. The pumping apparatus comprises a pumping chamber configured for receiving one or more fluids in defined proportions and for further delivering the received fluids. An outlet of the pumping apparatus is provided for outleting the fluid to be delivered. The outlet fluidically couples to a first position in the pumping chamber. The pumping apparatus further comprises a channel which fluidically couples on one side (or, in other words, with one end) to a second position in the pumping chamber and on the other side to the outlet. In operation of the pumping apparatus, a first portion of the delivered fluid (as outlet at the outlet) is received from the first position in the pumping chamber, and a second portion of the delivered fluid (as outlet at the outlet) is received from the second position in the pumping chamber.

In order to improve mixing of different fluid components in the fluid to be delivered at the outlet, one of the first and second positions is a spatial position within the pumping chamber where fluid components having a first property would tend to accumulate during operation of the pumping apparatus if such position were not coupled to the outlet, with such accumulation resulting from variations in the first property. By coupling the outlet to such position, an accumulation of fluid components can be reduced or even be avoided during operation of the pumping apparatus, thus leading to an improved mixing.

It is clear that (in particular due to dynamic behavior of fluids) the term “where” as used here in the context of “spatial position within the pumping chamber where fluid components having a first property would tend to accumulate” is not limited to a precise position but shall also encompass “in proximity” covering spatial positions close by.

It has been found by the present inventors that in some operation modes of the pumping apparatus, fluid components with variations in the first property (e.g. different density) tend to accumulate during operation in different spatial areas of the pumping chamber. E.g. in case the first property is density, fluid components being heavier than other fluid components (i.e. those with higher density) may settle down at the bottom or a lower part within in the pumping chamber, while the lighter fluid components (i.e. those with lower density) tend to accumulate, with respect to other fluid components, in an upper or top part or region of the pumping chamber, both under the influence of gravitational forces.

Such accumulation can occur just as well under ultra-high pressure conditions and even in pumping apparatus configurations being already optimized for reduction of dead volumes and/or dead-end areas. While this might go unnoticed during most of the time of operating the pumping apparatus, some fluid portions with deviant composition accumulated over time in such areas might come under certain conditions into the fluid at the outlet. This can lead to a sporadic variation in the composition of the (e.g. pressurized) fluid delivered downstream which can adversely influence a sample separation or measurement provided in an HPLC application and might even become visible e.g. as a noise signal detected by a detector of the HPLC system.

It has been found that such accumulated fluid components might be found in particular in the least disturbed areas or regions within the pumping chamber. E.g. in case of a reciprocating element reciprocating within the pumping chamber, such fluid components tend to accumulate in areas or regions being more distant from the reciprocating element. Similarly, regions or areas near sealing elements also tends to accumulate fluid components dependent on differences in the first property of the fluid components, in particular if there is a larger volume with lesser movement of the fluid there. E.g., the lower density fluid components may typically accumulate at upper regions within the pumping chamber, while higher density fluid components may accumulate at lower regions within the pumping chamber. Accordingly, the spatial positions within the pumping chamber where such fluid components having a lower density tend to accumulate typically are in the spatial region of an upper side of the pumping apparatus during operation. The spatial positions within the pumping chamber where such fluid components having a higher density tend to accumulate typically are in the spatial region of a lower side of the pumping apparatus during operation.

It goes without saying that dependent on the specific geometry as well as the specific mode of operation of the pumping apparatus, the segregation or separation of different fluid components might be more or less pronounced. There might be cases with an almost complete segregation of fluid components dependent on the first property. In other cases, for example, only the higher density fluid components accumulate at a lower region within the pumping chamber, or only the lower density fluid components accumulate at an upper region within the pumping chamber.

The first property preferably is a property, whereas its value for at least one of the fluid components is deviant from at least one of its average value, its value for one of the other components, and its value for majority of others of the fluid components in the pumping chamber. The first property preferably is one or more of: density, temperature, composition, and viscosity. It is advantageous to preferably force to the outlet or remove from the corresponding areas such components having the most deviant properties and tending to accumulate in more or less compact areas according to their properties.

Embodiments of the present invention can be beneficial irrespective on the type of the first property and/or the degree of separation and can lead to a significantly better mixture quality as well as to avoiding artifacts resulting from variations in fluid composition.

In an example with the first property being density, one of the first and second positions may be a spatial position within the pumping chamber wherein such fluid components having a lower density would tend to accumulate during operation of the pumping apparatus, and/or the other of the first and second positions is a spatial position within the pumping chamber wherein such fluid components having a higher density would tend to accumulate during operation of the pumping apparatus. However, such accumulation can be reduced or even avoided by coupling at least one of such positions to the outlet in accordance with embodiments of the present invention.

The multiple outlet ports in both of the aforementioned prior art documents JPS61258975A and US2013/0091935A1 are arranged at the same altitude level of the pump, so that composition variations resulting from an accumulation caused by variations in density cannot be reduced or suppressed effectively. In contrast thereto, embodiments of the present invention address for the issue of spatial variations in fluid composition, as resulting from accumulations caused by variations in fluid density, by configuring the pumping apparatus so that the outlet receives partial fluid flows being derived from different altitude levels within the pumping chamber.

Properties other than density may directly or indirectly also lead to segregation or incomplete mixing of the components of the fluid (s). E.g. temperature differences could lead to density differences and thus indirectly facilitate separation and accumulation of the liquid portions with different temperature and thus different density. Composition differences may be a reason for viscosity and density differences and thus an indirect reason for the segregation, accumulation phenomena and inferior liquid mixing. Viscosity differences originating from different composition or temperature of the liquid can cause some property-specific behavior known as e.g. the so-called viscous fingering, which can lead to segregation of the liquid portions and to preferred accumulation of the portions with high and low viscosity in different areas.

In one embodiment, the pumping apparatus comprises a first opening into the pumping chamber at the first position in the pumping chamber, and a second opening into the pumping chamber at the second position in the pumping chamber. The outlet is fluidically coupled to the first opening as well as to the second opening. In such embodiment, the channel is provided external to the pumping chamber, e.g. within a housing of the pumping apparatus which may also house the pumping chamber, or by providing adequate connections as readily known in the art, such as capillaries, tubes, channels, etc.

In another embodiment, the channel is provided inside or within the pumping chamber. Preferably, a channel forming element can be used which is to be located within the pumping chamber and configured for providing the channel. Any arrangement or combination of elements may be used to form the channel within the pumping chamber, e.g. by separating a compartment within the pumping chamber as the channel.

According to another embodiment of the present invention, a pumping apparatus is configured for delivering a fluid. The pumping apparatus comprises a pumping chamber configured for receiving one or more fluids in defined proportions and for further delivering the received fluids. An outlet is provided for outleting the fluid to be delivered. The outlet is fluidically coupling to a first position in the pumping chamber. The pumping apparatus further comprises a channel forming element located within the pumping chamber and which is configured for providing a channel. The channel fluidically couples, on one side, to a second position in the pumping chamber and, on the other side, to the outlet. In operation, a first portion of the fluid, as outlet at the outlet, is received from the first position in the pumping chamber, and a second portion of the fluid, as outlet at the outlet, is received from the second position in the pumping chamber.

In one embodiment, the channel forming element has a ring shape. Alternatively or in addition, the channel forming element may comprise the channel being integrally formed into the channel forming element.

In one embodiment, the channel forming element is configured for providing the channel by at least a part of its outer surface. In one embodiment, the channel forming element is configured for providing or forming the channel in a way that at least part of a surface of the channel forming element represents at least a part of a wall surface of the channel. Preferably, the channel forming element comprises in its outer surface a recess, groove, chamfer or the like for forming the channel. When the channel forming element is attached to an internal surface or a wall of the pumping chamber, such recess, groove, chamfer, etc. forms the channel in conjunction with at least a part of the internal surface or wall of the pumping chamber.

The channel forming element may comprise at least one coupling channel, wherein each coupling channel is configured for fluidically coupling to one of the first and second positions in the pumping chamber. This may be in particular useful in case the channel is provided or formed in conjunction with an opposing wall of the pumping chamber, so that each coupling channel might reach through the channel forming element.

In an alternate embodiment, the channel forming element provides such at least one coupling channel in conjunction with a part of the wall of the pumping chamber when the channel forming element is attached to such wall of the pumping chamber. This may be provided by a recess, chamfer, groove, or the like in an outer surface of the channel forming element. Each coupling channel is configured for fluidically coupling to one of the first and second positions in the pumping chamber.

In one embodiment, the channel forming element has a ring shape and comprises a chamfer or groove configured for forming the channel in conjunction with a part of a wall of the pumping chamber when the channel forming element is (preferably immovably) placed or attached (preferably to the wall) of the pumping chamber. The channel forming element further comprises a first coupling channel for fluidically coupling to the first position in the pumping chamber, and a second coupling channel for fluidically coupling to the second position in the pumping chamber. The term “attached” as used here may describe the placement of one element relative to the other so that their mobility relative to each other is limited or suppressed.

The various embodiments of the channel forming element allow easily adjusting and configuring the channel to the specific applications and requirements as well as to different operation modes of the pumping apparatus. The channel forming element may preferably be configured to be replaceable or exchangeable.

In one embodiment, the channel forming element is configured as a permeable (preferably porous) element thus providing a plurality of flow path channels fluidically coupling on one side to the outlet and on the other side to multiple different positions or a distributed area in the pumping chamber. In operation, the fluid as outlet at the outlet is thus comprised of fluid portions received from the multiple different positions in the pumping chamber. Such permeable channel forming element may be preferably configured to result in parallelized outlet and/or a good mixing of the fluid portions from the different positions in the pumping chamber, e.g. by adequately designing the geometry of the flow path channels, for example with respect to the flow resistance. In one embodiment, the permeable element is provided as a frit.

In one embodiment, the pumping apparatus comprises an inlet opening into the pumping chamber. The inlet is configured for receiving the one or more fluids in defined proportions.

In one embodiment, the pumping apparatus comprises an actuating element, which is configured for repeatedly varying a free volume within the pumping chamber for sucking in as well as outputting (and preferably pressurizing) the received fluids. This may be provided by a reciprocating element configured for reciprocating within the pumping chamber thus displacing the received fluids. The actuating element preferably is a pressurizing element configured for pressurizing the received fluids.

In one embodiment, a first flow path is provided between the first position in the pumping chamber and the outlet. A second flow path is provided between the second position in the pumping chamber and the outlet. The first and second flow paths are preferably configured so that the partial flows taken from the first position and the second position are substantially matched or are in a given ratio.

In one embodiment, a first flow resistance of the first flow path may be configured to substantially match or be in a given ratio to a second flow resistance of the second flow path. Preferably, the partial flows taken from the first position and the second position are substantially matched or in a given ratio. The respective flow resistance might be defined as from the first/second position to a joining point of the first and second flow paths. The outlet might then be defined and understood as that position at which the fluid flows in one channel (or flow path) only or, in other words, where the first and second flow paths are joined into one flow path.

In one embodiment, a first flow resistance of the flow path constituted by a first channel between the first position in the pumping chamber and the outlet is configured to substantially match or be in a given ratio to a second flow resistance constituted by a second channel between the second position in the pumping chamber and the outlet, so that the partial flows taken from the first position and the second position are substantially matched or in a given ratio.

In one embodiment, one of the first and second positions is located at or at least close to a location having minimum value in vertical height of the pumping chamber during its operation. In one embodiment, one of the first and second positions is located at or at least close to a maximum value in vertical height of the pumping chamber during its operation. Preferably, one of the first and second positions is located at or at least close to a location having the minimum value in vertical height while the other one of the first and second positions is located at or at least close to a location having the maximum value in vertical height of the pumping chamber during its operation. Such embodiments may allow receiving partial flows from the minimum height region within the pumping chamber where the higher density fluid components tend to accumulate, while the other partial flow is received from the maximum height region within the pumping chamber where typically the lower density fluid components accumulate.

The pumping apparatus according to any of the aforedescribed embodiments may be part of a sample separation system configured for separating compounds of a sample fluid in a mobile phase. Such fluid separation system comprises a mobile phase drive adapted to drive the mobile phase through the fluid separation system, and a separation unit, such as a chromatographic column, which is configured for separating compounds of the sample fluid in the mobile phase. In such embodiments, the mobile phase drive comprises the pumping apparatus of the aforedescribed embodiments.

The sample separation system may comprise one or more of the following: a fluid proportioning unit for providing one or more fluids in defined proportions to the pumping apparatus, a sample injector to introduce the sample fluid into the mobile phase, a detector for detecting separated compounds of the sample fluid, a collection unit for collecting separated compounds of the sample fluid, a data processing unit configured for processing data received from the fluid separation system, a degassing apparatus for the degassing the mobile phase.

Another aspect of the present invention relates to a method of delivering a fluid by using a pumping apparatus. The pumping apparatus comprises a pumping chamber configured for receiving one or more fluids in defined proportions and for further delivering the received fluids, and an outlet which is fluidically coupling to a first position in the pumping chamber and provided for outleting the fluid to be delivered. The pumping apparatus further comprises a channel which is fluidically coupled, on one side, to a second position in the pumping chamber and, on the other side, to the outlet, so that during operation of the pumping apparatus a first portion of the delivered fluid, as outlet at the outlet, is received from the first portion in the pumping chamber, and a second portion of the delivered fluid, as outlet at the outlet, is received from the second position in the pumping chamber.

The method comprises the step of positioning the pumping apparatus so that one of the first and second positions is a spatial position within the pumping chamber where fluid components characterized by a first property would tend to accumulate during operation of the pumping apparatus if such position were not coupled to the outlet, with such accumulation resulting from variations in the first property.

In case the first property is density, the pumping apparatus may be positioned so that one of the first and second positions is a spatial position within the pumping chamber, wherein such fluid components having a lower density tend to accumulate during operation of the pumping apparatus, and the other of the first and second positions is a spatial position within the pumping chamber, wherein such fluid components having a higher density tend to accumulate during operation of the pumping apparatus.

Embodiments of the present invention might be embodied based on most conventionally available HPLC systems, such as the Agilent 1220, 1260 and 1290 Infinity LC Series or the Agilent 1100 HPLC series (all provided by the applicant Agilent Technologies—see www.agilentcom—which shall be incorporated herein by reference).

One embodiment of an HPLC system comprises a pumping apparatus having a piston for reciprocation in a pumping chamber (also referred to as pump working chamber) to compress liquid in the pump working chamber to a high pressure at which compressibility of the liquid becomes noticeable.

One embodiment of an HPLC system comprises a proportioning valve configured to selectively connect a fluid line, which is preferably a fluid intake line, to the selectable solvent sources or solvent source lines on one side and to the inlet line of the pumping apparatus on the other side. The proportioning valve, which also may be called a multiplexing valve, may be configured to provide portions or packets of the different solvents into a common chamber or common line in the desired ratio. The provided solvent packets may have significantly different chemical and physical properties.

One embodiment of an HPLC system comprises two pumping apparatuses coupled either in a serial or parallel manner. In the serial manner, as disclosed in EP 309596 A1, an outlet of the first pumping apparatus is coupled to an inlet of the second pumping apparatus, and an outlet of the second pumping apparatus provides an outlet of the pump. In the parallel manner, an inlet of the first pumping apparatus is coupled to an inlet of the second pumping apparatus, and an outlet of the first pumping apparatus is coupled to an outlet of the second pumping apparatus, thus providing an outlet of the pump. In either case, a liquid outlet of the first pumping apparatus is phase shifted, preferably essentially 180 degrees, with respect to a liquid outlet of the second pumping apparatus, so that only one pumping apparatus is supplying into the system while the other is intaking liquid (e.g. from the supply), thus allowing to provide a continuous flow at the output. However, it is clear that also both pumping apparatuses might be operated in parallel (i.e. concurrently), at least during certain transitional phases e.g. to provide a smooth(er) transition of the pumping cycles between the pumping apparatuses. The phase shifting might be varied in order to compensate pulsation in the flow of liquid as resulting from the compressibility of the liquid and from the reciprocate nature of the liquid delivery. It is also known to use three piston pumps having about 120 degrees phase shift.

The mobile phase (or eluent) can be either a pure solvent or a mixture of different solvents. It can be chosen e.g. to modulate the retention of the compounds of interest and/or the amount of mobile phase to run the chromatography. The mobile phase can also been chosen so that the different compounds can be separated effectively. The mobile phase might comprise an organic solvent like e.g. methanol or acetonitrile, often diluted with water. For gradient operation water and organic solvent may be delivered in separate vessels, from which the gradient pump delivers a programmed blend to the system. Other commonly used solvents may be isopropanol, THF, hexane, ethanol and/or any combination thereof or any combination of these with aforementioned solvents.

The sample fluid might comprise any type of process liquid, natural sample like juice, body fluids like plasma or it may be the result of a reaction like from a fermentation broth.

The fluid is preferably a liquid but may also be or comprise a gas and/or a supercritical fluid (as e.g. used in supercritical fluid chromatography—SFC—as disclosed e.g. in U.S. Pat. No. 4,982,597 A).

The pressure in the mobile phase might range from 2-200 MPa (20 to 2000 bar), in particular 10-150 MPa (100 to 1500 bar), and more particular 50-120 MPa (500 to 1200 bar).

The HPLC system might further comprise a sampling unit for introducing the sample fluid into the mobile phase stream, a detector for detecting separated compounds of the sample fluid, a fractionating unit for outputting separated compounds of the sample fluid, or any combination thereof. Further details of HPLC system are disclosed with respect to the aforementioned Agilent HPLC series, provided by the applicant Agilent Technologies, under www.agilent.com which shall be in cooperated herein by reference.

Embodiments of the invention can be supported by one or more suitable software programs, which can be stored on or otherwise provided by any kind of data carrier, and which might be executed in or by any suitable data processing unit. Software programs or routines can be preferably applied in or by the control unit.

BRIEF DESCRIPTION OF DRAWINGS

Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more detailed description of embodiments in connection with the accompanied drawing(s). Features that are substantially or functionally equal or similar will be referred to by the same reference sign(s). The illustration in the drawing is schematically.

FIG. 1 shows a liquid separation system 10, in accordance with embodiments of the present invention, e.g. used in high performance liquid chromatography (HPLC).

FIG. 2 shows in cross sectional three dimensional view an embodiment of a pumping apparatus 200.

FIG. 3 illustrates in a schematic cross sectional view an effect to be addressed by the present invention.

FIG. 4 illustrates in schematic cross sectional view the principle of a first embodiment according to the present invention.

FIG. 5 shows another embodiment similar to the embodiment of FIG. 2, however, with an additional channel 410 provided in accordance with the embodiment of FIG. 4.

FIG. 6 illustrates a schematic cross sectional view of another embodiment according to the present invention.

Referring now in greater detail to the drawings, FIG. 1 depicts a general schematic of a liquid separation system 10. A pump 20 receives a mobile phase from a solvent supply 25, typically via a degasser 27, which reduces the amount of dissolved gases in the mobile phase. The pump 20—as a mobile phase drive—drives the mobile phase through a separating device 30 (such as a chromatographic column) comprising a stationary phase. A sampling unit 40 can be provided between the pump 20 and the separating device 30 in order to subject or add (often referred to as sample introduction) a sample fluid into the fluid path. The stationary phase of the separating device 30 is adapted for separating compounds of the sample liquid. A detector 50 is provided for detecting separated compounds of the sample fluid. A fractionating unit 60 can be provided for outputting separated compounds of sample fluid.

While the mobile phase can comprise one solvent only, it may also be mixed from plural solvents. Such mixing might be a low pressure mixing and provided upstream of the pump 20, so that the pump 20 already receives multiple solvents, which might be completely or partially mixed. The pump 20 pumps the solvents or preferably their mixture as the mobile phase. Alternatively, the pump 20 might be comprised of plural individual pumping units, with plural of the pumping units each receiving and pumping a different solvent or mixture, so that the mixing of the mobile phase (as received by the separating device 30) occurs at high pressure and downstream of the pump 20 (or as part thereof). The composition (mixture) of the mobile phase may be kept constant over time, the so called isocratic mode, or varied over time, the so called gradient mode.

A data processing unit 70, which can be a conventional PC or workstation, might be coupled (as indicated by the dotted arrows) to one or more of the devices in the liquid separation system 10 in order to receive information and/or control operation. For example, the data processing unit 70 might control operation of the pump 20 (e.g. setting control parameters) and receive therefrom information regarding the actual working conditions (such as output pressure, flow rate, etc. at an outlet (240) of the pump). The data processing unit 70 might also control operation of the solvent supply 25 (e.g. setting the solvent/s or solvent mixture to be supplied) and/or the degasser 27 (e.g. setting control parameters such as vacuum level) and might receive therefrom information regarding the actual working conditions (such as solvent composition supplied over time, flow rate, vacuum level, etc.). The data processing unit 70 might further control operation of the sampling unit 40. The separating device 30 might also be controlled by the data processing unit 70 (e.g. selecting a specific flow path or column, setting operation temperature, etc.), and send—in return—information (e.g. operating conditions) to the data processing unit 70. Accordingly, the detector 50 might be controlled by the data processing unit 70 (e.g. with respect to spectral or wavelength settings, setting time constants, start/stop data acquisition), and send information (e.g. about the detected sample compounds) to the data processing unit 70. The data processing unit 70 might also control operation of the fractionating unit 60 (e.g. in conjunction with data received from the detector 50) and provides data back.

FIG. 2 shows in cross sectional three dimensional view an embodiment of a pumping apparatus 200. Pump 20 (as depicted in FIG. 1) may comprise two of such (or similar) pumping apparatuses 200, preferably coupled in serial manner as readily known in the art. The pumping apparatus 200 has an inlet 210 opening into a pumping chamber 220 wherein a reciprocating element 230, preferably a piston, is provided for reciprocating within the pumping chamber 220 for displacing fluids received from the inlet 210 or for providing free space (drawing) and receiving the fluid from the inlet 210 respectively. An outlet 240 is fluidically coupled to the pumping chamber 220 for outleting the displaced (and thus pressurized) fluid.

Not shown in FIG. 2 are respective valves respectively coupling to the inlet 210 and to the outlet 240 to allow sucking in of fluid (during a leftwards movement of the piston 230 as depicted in FIG. 2) and a pressurizing and discharge of the pressurized fluid during a rightwards movement of the piston 230. Such valves as well as other details and configurations, e.g. the solvent mixing and proportioning, are disclosed and described in detail in the aforementioned WO2013013717A2 by the same applicant and inventors, which shall be incorporated herein by reference.

FIG. 2 further shows a seal 250 for sealing the pumping chamber 220 together with the respective portion of the piston 230 reaching into the pumping chamber 220 as well as being in connection with the seal 250. The pumping chamber 220 together with the inlet 210 and the outlet 240 are provided within a pump head 260 which in this embodiment is a solid metal block with the pumping chamber 220, the inlet 210 and the outlet 240 being provided as bore holes.

The pump head 260 is attached to a mechanical part 270 which bears the piston 230, optionally a return mechanism 280 (here: a spring for forcing the piston 230 to follow the drive during its backwards direction movement not shown in FIG. 2).

FIG. 3 illustrates in a schematic cross sectional view an effect to be addressed by the present invention. At the inlet 210, “packets” of different solvents are received and sucked in under the influence of the movement of the piston 230 into the pumping chamber 220. In the example of FIG. 3, the inlet 210 receives packets of a first solvent 310 and a second solvent 320, which arrive alternatingly but with varying proportions dependent on the desired composition of the pressurized fluid to be output at the outlet 240. In this example, solvent 310 shall have a higher density than solvent 320. For example, solvent 310 can be water (1 g/ml) and solvent 320 can be one of acetonitrile or methanol (both about 0.8 g/ml).

During operation of the pumping apparatus 200, portions of the solvent 310 or portions of the mixture with occasionally higher content of the solvent 310 than in the environment having a higher density might accumulate in a lower region 330 of the pumping chamber 220, as schematically depicted with reference numeral 340. It is to be understood that most of the solvent packets 310 and 320 will be mixed within the pumping chamber 220 to a very high extent, so that the pressurized fluid discharged at the outlet 240, indicated by arrow 350, is substantially homogeneous and well mixed. Nevertheless, region 330 may still accumulate a certain amount of higher density fluid components, as indicated with reference numeral 340, such as solvent 310 or incompletely mixed fluid portions with relatively higher content of more dense component, thus having higher density, as result of gravitational force.

Under certain conditions or in certain operation modes, a random amount of the accumulated portion 340 might be discharged into the outlet 240 thus leading to an undesired variation in the fluid composition at outlet 240, which can adversely influence the measurement quality or even lead to “ghost peaks” in the chromatogram.

As illustrated in FIG. 3, which substantially represents a typical prior art embodiment where fluid components actually tend to accumulate (e.g. at position or region 340) during operation of the pumping apparatus, the outlet 240 fluidically only couples to a position or region 350, here at an upper side 360 of the pumping chamber, but not to the position or region 340 of accumulated fluid portions with higher density. It goes without saying, that the same principle applies, however, the other way around, in case the outlet 240 is arranged at the lower portion 330 of the pumping chamber 220. In such case, solvent portions with a lower density can accumulate in the upper area 360 of the pumping chamber 220, for example in the indicated position 350.

FIG. 4 illustrates in schematic cross sectional view the principle of a first embodiment according to the present invention. In contrast to FIG. 3, the outlet 240 of the embodiment in FIG. 4 is coupled not only via the (first) opening 370 to the pumping chamber 220, but further comprises a second opening 400 into the pumping chamber 220, and a channel 410 which couples to a tube or channel 420 exiting from the first opening 370, thus forming the outlet 240.

As apparent from the schematic view in FIG. 4, while the first opening 370 is provided in the upper region 360 within the pumping chamber, i.e. such region within the pumping chamber 220 having the highest altitude during operation of the pump, the second opening 400 is provided in the lower region 330 of the pumping chamber, i.e. in a region having the lowest altitude within the pumping chamber 220 during operation. It is clear that the first openings 370 and second openings 400 need not necessarily be provided at the absolute highest or lowest altitude, respectively, within the pumping chamber. However, such openings 370 and 400 should be provided in a proximity to the regions within the pumping chamber 220 where fluid components differing in their property (such as density) from the bulk of the content of the chamber 220 would tend to accumulate during operation (e.g. under the influence of gravitational forces), if there were no such opening. By providing the two openings 370 and 400 coupling to such regions where fluid components would tend to accumulate during operation of the pumping apparatus 200 if the outlet where not coupled to such regions 340 and 350, embodiments of the present invention allow to significantly improve mixing of the pressurized fluid supplied at the outlet 240 and in particular allow reducing the effect of sporadic fluid compositions variations resulting from accumulated fluid components within the pumping chamber 220.

By providing the openings 370 and/or 400, accumulation (e.g. in the regions 340 and/or 350) of the fluid components during operation of the pumping apparatus 200 is at least reduced and in best case even completely avoided. The effect of the present invention may be verified by (e.g. temporarily) blocking one of the openings 370 and 400 and comparing the mixing properties/accuracy before and after blocking.

While the openings 370 and 400 are preferably provided at regions of the highest and lowest altitude within the pumping chamber 220 (in order to address typical regions of fluid components accumulation resulting from density variations), it is clear that dependent on the specific embodiment and shape of the pumping chamber 220 other locations for providing the openings 370 and 400 might be more adequate or better suited. For example, regions close to the seal 250 might be more or alternatively suitable.

In order to provide a good mixing of the fluid components within the pressurized fluid as outlet at the outlet 240, the flow paths between the pumping chamber and the outlet 240 are preferably configured so that the partial flows are substantially matched or in a given ratio. It might be essential that the major portion of the accumulated components with deviant first property, e.g. density, is removed from the accumulation areas as rapidly as possible, preferably within each single reciprocation of the pump drive. Therefore it might be assumed that approximately equal partial flow rates might be a preferable embodiment. However depending on specific geometry of such upmost and lowest locations within a pumping chamber or even on the specific properties of the mixing process it might also be advantageous to preferably remove (i.e. provide to outlet) the “lightest” or the “heaviest” component by means of adjusting the ratio of the said partial flows.

FIG. 5 shows another embodiment similar to the embodiment of FIG. 2, however, with an additional channel 410 provided in accordance with the embodiment of FIG. 4. The flow paths into and from the pumping chamber 220 are only illustrated schematically. In this embodiment, the flow path to the inlet 210 comprises a proportioning valve 500 schematically illustrated for proportioning or blending up to four solvents A, B, C and D.

A first flow path 510 between the pumping chamber 220 and the outlet 240 is comprised of a bore 520 opening into the pumping chamber 220 at a top side of the pumping chamber 220 and the channel 420. The channel 420 between the bore 520 and the outlet 240 is only schematically illustrated in FIG. 5 and might be embodied as known in the art, e.g. by a capillary, tube, microfluidic network, etc.

A second bore 530 through the pump head 260 is opening into the pumping chamber 220 at a lower region within the pumping chamber 220, or in other words at an opposing altitude with respect to the bore 520. While the bore 520 opens substantially in a highest altitude region of the pumping chamber 220, the bore 530 opens substantially in a lowest altitude region of the pumping chamber 220. The channel 410 coupling from the bore 530 to the outlet 240 is also illustrated here only schematically. The bore 530 together with the channel 410 provide a second flow path 540 between the pumping chamber 220 and the outlet 240.

FIG. 6 illustrates a schematic cross sectional view of another embodiment according to the present invention. In this embodiment, the channel 410 is provided internal within the pumping chamber 220 by an adequately shaped channel forming element 600. In the embodiment of FIG. 6, the channel forming element 600 is provided as a ring 600 which is to be placed into the pumping chamber 220. While the left hand side drawing of FIG. 6 shows the pumping apparatus 200 (or better to say a part thereof), the right hand side drawing in FIG. 6 only shows the ring 600 in front side view. The ring 600 on the left side drawing shows the ring 600 in cross sectional view along line B (indicated on the left hand side drawing).

The ring 600 has a chamfer 610 (visible best on the left hand side drawing of FIG. 6), so that the channel 410 is provided between the side walls of the pumping chamber 220 and the ring 600 when the ring 600 is closely attached to the walls of the pumping chamber 220. In the embodiment of FIG. 6, the ring 600 has a first sealing surface 620 schematically indicated by a dot, and a second sealing surface 630, also schematically indicated by a dot. Such ring or differently shaped channel forming element 600 can be squeezed into the pumping chamber 220, which might have an appropriate recess or profile. The channel forming element 600 might also be fixed to the pumping chamber 220 or its constituting elements (such as seal or other parts) e.g. by gluing, soldering, welding, diffusion bonding or other binding process.

It is clear that other embodiments for providing the channel 410 can be applied accordingly, for example by providing a groove or any other kind of recess into such ring 600. Alternatively, the channel might also be provided within (i.e. internally) such ring 600.

In case the channel 410 does not have a direct access to the respective area of accumulated fluid portions, e.g. region 340 or region 350 (see FIG. 3), the ring 600 might comprise one or more adequate coupling channels such as a bore 640 fluidically coupling the channel 410 to the region 340. Accordingly, the embodiment of FIG. 6 comprises a second bore 650 fluidically coupling to the region 350. The outlet 240 is therefore coupled via the bore 650 to the region 350 (which corresponds to the first flow path 510 in FIG. 5) and couples via the channel 410 and the bore 640 to the region 340 (corresponding to the second flow path 540 in FIG. 5).

In one embodiment, the channel forming element is configured as a permeable (preferably porous) element thus providing a plurality of flow path channels fluidically coupling on one side to the outlet and on the other side to multiple different positions in the pumping chamber, which preferably include the upper and the lower regions of the pump chamber. In operation, the pressurized fluid as outlet at the outlet is thus comprised of fluid portions received from the multiple different positions in the pumping chamber. Such permeable channel forming element may be preferably configured to result in a good mixing of the fluid portions from the different positions in the pumping chamber, e.g. by adequately designing the geometry of the flow path channels, for example with respect to the flow resistance. In one embodiment, the permeable element is provided as a frit. In an alternative embodiment such element might be constituted as a micro-channel plate. In still another embodiment such element might be constituted as metal, polymer or resin wool or foam.

In each of the aforementioned embodiments of FIGS. 4-6, the first 510 and second 520 flow paths (i.e. the flow paths between the pumping chamber 220 and the outlet 240) are preferably configured so that the partial flows provided by both flow paths are substantially matched or in a given ratio, e.g. by substantially matching flow resistances. In embodiments comprising the additional channels 410 provided external to the pumping chamber 220 (FIGS. 4-5), the matching of the partial flows is preferably provided by adjustment of the dimensions of the flow conducting elements (e.g. capillary tubes). In embodiments comprising the additional channels 410 provided internal within the pumping chamber 220 (e.g. the ring 600 in FIG. 6), the matching of the partial flows is preferably provided by appropriate choice of the dimensions, i.e. shape, cross-section and length of the partial flow paths, e.g. by the diameters of the bores 640 and 650.

In a further embodiment the connections (or parts thereof) from the regions 340, 350 to the outlet 240 might be constituted of slits or groves e.g. in one of the pumping chamber 220 wall, the channel forming ring or between these elements.

In still another embodiment the pumping chamber 220 might have multiple upper and/or multiple lower regions, where the deviant solvent might preferably accumulate. Such embodiments may comprise plural openings (such as opening 400) and coupling channels (such as channel 410), each addressing a single of the “extremum” regions within the pumping chamber 220.

While the aforedescribed embodiments have been described in particular with respect to accumulations resulting from variations in density, it is clear that the same principle can be applied, mutatis mutandis, with respect to other properties of the fluid components, such as temperature and viscosity. If the first property leads to separation and/or segregation of the liquid components indirectly, e.g. by influencing density (as e.g. temperature does), then positioning principles for the additional openings are similar to those addressing the case if the first property is density. If the segregation is driven directly by a different property, such as viscosity, the additional opening should be placed in or near the areas where the most viscous as well as where the least viscous components are preferably accumulated according to the geometry of the chamber and the flow distribution within the chamber. 

1. A pumping apparatus configured for delivering a fluid, the pumping apparatus comprising: a pumping chamber being configured for receiving one or more fluids in defined proportions and for further delivering the received fluids, an outlet, fluidically coupling to a first position in the pumping chamber, for outleting the fluid to be delivered, a channel fluidically coupling on one side to a second position in the pumping chamber and on the other side to the outlet so that—in operation—a first portion of the delivered fluid as outlet at the outlet is received from the first position in the pumping chamber, and a second portion of the delivered fluid as outlet at the outlet is received from the second position in the pumping chamber, characterized in that one of the first and second positions is a spatial position within the pumping chamber where fluid components having a first property would tend to accumulate during operation of the pumping apparatus if such position were not coupled to the outlet, with such accumulation resulting from differences of the first property of the fluid components.
 2. The apparatus of claim 1, comprising at least one of: the first property is a property, whereas its value for at least one of the fluid components is deviant from at least one of its average value, its value for one of the other components, and its value for majority of others of the fluid components in the pumping chamber; the first property is at least one of density, temperature, viscosity, composition.
 3. The apparatus of claim 1 and wherein the first property is density, comprising at least one of: one of the first and second positions is a spatial position within the pumping chamber, wherein such fluid components having a lower density would tend to accumulate during operation of the pumping apparatus and/or the other of the first and second positions is a spatial position within the pumping chamber, wherein such fluid components having a higher density would tend to accumulate during operation of the pumping apparatus; the spatial position within the pumping chamber, where such fluid components having a lower density tend to accumulate, is in the spatial region of an upper side of the pumping chamber during operation, and the spatial position within the pumping chamber, wherein such fluid components having a higher density tend to accumulate, is in the spatial region of a lower side of the pumping chamber during operation.
 4. The apparatus of claim 1, further comprising a first opening in the pumping chamber at the first position in the pumping chamber, and a second opening in the pumping chamber at the second position in the pumping chamber, wherein the outlet is fluidically coupled to the first opening and via the channel to the second opening.
 5. The apparatus of the claim 4, wherein the channel is at least partly provided within a housing of the pumping apparatus, and the housing also houses the pumping chamber.
 6. The apparatus of claim 1, further comprising a channel forming element located within the pumping chamber and being configured for providing the channel.
 7. A pumping apparatus configured for delivering a fluid, the pumping apparatus comprising: a pumping chamber being configured for receiving one or more fluids in defined proportions and for further delivering the received fluids, an outlet, fluidically coupling to a first position in the pumping chamber, for outleting the fluid to be delivered, characterized by a channel forming element located within the pumping chamber and being configured for providing a channel, wherein the channel fluidically couples on one side to a second position in the pumping chamber and on the other side to the outlet, so that—in operation—a first portion of the fluid as outlet at the outlet is received from the first position in the pumping chamber, and a second portion of the fluid as outlet at the outlet is received from the second position in the pumping chamber.
 8. The apparatus of claim 7, comprising at least one of: the channel forming element has a ring shape; the channel forming element comprises the channel integrally formed into the channel forming element; the channel forming element is configured for providing or forming the channel in a way that at least part of a surface of the channel forming element represents at least a part of a wall surface of the channel; the channel forming element comprises in its outer surface at least one of a recess, a groove, and a chamfer, configured for forming the channel in conjunction with at least a part of an internal surface or a wall of the pumping chamber when the channel forming element is attached to the internal surface or wall of the pumping chamber; the channel forming element comprises a chamfer configured for forming the channel in conjunction with a part of a wall of the pumping chamber when the channel forming element is attached to the wall of the pumping chamber; the channel forming element comprises at least one coupling channel, each configured for fluidically coupling the channel to one of the first and second positions in the pumping chamber; the channel forming element provides at least one coupling channel in conjunction with a part of a wall of the pumping chamber when the channel forming element is attached to the wall of the pumping chamber, each coupling channel being configured for fluidically coupling the channel to one of the first and second positions in the pumping chamber; the channel forming element has a ring shape and comprises a chamfer configured for forming the channel in conjunction with a part of a wall of the pumping chamber when the channel forming element is attached to the wall of the pumping chamber, the channel forming element further comprises a first coupling channel for fluidically coupling the channel to the first position in the pumping chamber, and a second coupling channel for fluidically coupling to the second position in the pumping chamber.
 9. The apparatus of claim 7, wherein the channel forming element is a permeable, preferably porous, element providing a plurality of flow channels fluidically coupling on one side to the outlet and on the other side to multiple different positions in the pumping chamber, so that—in operation—the fluid as outlet at the outlet is comprised of fluid portions received from the multiple different positions in the pumping chamber.
 10. The apparatus of claim 1, comprising at least one of: an inlet opening into the pumping chamber and being configured for receiving the one or more fluids in defined proportions; an actuating element, preferably a pressurizing element, configured for repeatedly varying a free volume within the pumping chamber for displacing, preferably pressurizing, the received fluids; a reciprocating element configured for reciprocating within the pumping chamber for displacing the received fluids.
 11. The apparatus of claim 1, comprising at least one of: a first flow path between the first position in the pumping chamber and the outlet and a second flow path between the second position in the pumping chamber and the outlet are configured so that the partial flows taken from the first position and the second position are substantially matched or are in a given ratio; a first flow resistance of a first flow path between the first position in the pumping chamber and the outlet is configured to substantially match or be in a given ratio to a second flow resistance of the channel providing a second flow path between the second position, in the pumping chamber and the outlet; a first flow resistance of the flow path between the first position in the pumping chamber and the outlet is configured to substantially match or be in a given ratio to a second flow resistance of the channel providing the flow path between the second position in the pumping chamber and the outlet, so that the partial flows taken from the first position and the second position are substantially matched or in a given ratio; a first flow resistance of the flow path constituted by a first channel between the first position in the pumping chamber and the outlet is configured to substantially match or be in a given ratio to a second flow resistance constituted by a second channel between the second position in the pumping chamber and the outlet, so that the partial flows taken from the first position and the second position are substantially matched or in a given ratio.
 12. The apparatus of claim 1, comprising at least one of: one of the first and second positions is located at or at least close to a location with minimum value in vertical height of the pumping chamber during its operation; one of the first and second positions is located at or at least close to a location with maximum value in vertical height of the pumping chamber during its operation.
 13. A sample separation system for separating compounds of a sample fluid in a mobile phase, the fluid separation system comprising: a mobile phase drive adapted to drive the mobile phase through the fluid separation system, the mobile phase drive comprising the pumping apparatus of claim 1, and a separation unit, preferably a chromatographic column, adapted for separating compounds of the sample fluid in the mobile phase.
 14. The sample separation system of claim 13, further comprising at least one of: a fluid proportioning unit configured for providing one or more fluids in defined proportions to the pumping apparatus, a sample injector adapted to introduce the sample fluid into the mobile phase; a detector adapted to detect separated compounds of the sample fluid; a collection unit adapted to collect separated compounds of the sample fluid; a data processing unit adapted to process data received from the fluid separation system; a degassing apparatus for degassing the mobile phase.
 15. A method of delivering a fluid by using a pumping apparatus comprising: a pumping chamber being configured for receiving one or more fluids in defined proportions and for further delivering the received fluids, an outlet, fluidically coupling to a first position in the pumping chamber, for outleting the fluid to be delivered, and a channel fluidically coupling on one side to a second position in the pumping chamber and on the other side to the outlet, so that—in operation—a first portion of the delivered fluid as outlet at the outlet is received from the first position in the pumping chamber, and a second portion of the delivered fluid as outlet at the outlet is received from the second position in the pumping chamber, the method comprising the step of: positioning the pumping apparatus so that one of the first and second positions is a spatial position within the pumping chamber where fluid components having a first property would tend to accumulate during operation of the pumping apparatus if such position were not coupled to the outlet, with such accumulation resulting from variations in the first property.
 16. The method of claim 15, wherein the first property is density, the method further comprising: positioning the pumping apparatus so that one of the first and second positions is a spatial position within the pumping chamber, wherein such fluid components having a lower density tend to accumulate during operation of the pumping apparatus, and the other of the first and second positions is a spatial position within the pumping chamber, wherein such fluid components having a higher density tend to accumulate during operation of the pumping apparatus. 